Cyclopropyl 1,2,4-oxadiazolyldiazines

ABSTRACT

Preparation of 1,2,4-oxadiazolyldiazines by the reaction of cyclopropylcarboxylic acid anhydride and a diazinecarboxamidoxime at an elevated temperature. Other methods are also described. The compounds are useful for their central nervous system depressant activity.

ilnited States Patent 91 Fanshavve et al.

[45] Dec. 311, 19741 CYCLOPROPYL l,2,4-()XADIAZOLYLDIAZINES Inventors:William Joseph Fanshawe, Pearl River, N.Y.; Sidney Robert Safir, RiverEdge, NJ.

Assignee: American Cyanamid Company,

Stanford, Conn.

Filed: Apr. 2, 1973 Appl. No.: 347,307

Related US. Application Data Division of Ser. No. 288,219, Sept. ll,1972, Pat. No. 3,770,739.

US. Cl 260/256.4 R, 260/250 BN,

'7 Int. Cl C07d 51/36 Field of Search 260/256.4 R

[56] References Cited UNITED STATES PATENTS 3,478,049 11/1969 Von Eschet a1. 260/256.4 R

OTHER PUBLICATIONS Behr, Heterocyclic Compounds," (Wiley), 1962, p. 245.

Primary ExaminerRichard J. Gallagher Assistant Examiner-James H.Turnipseed Attorney, Agent, or Firm-E. Y. Miller 5 7] ABSTRACTCYCLOPROPYL l,2,4-OXADIAZOLYLDIAZINES This application is a division ofour application Ser. No. 288,2l9, filed Sept. 11, 1972 now US. Pat. No.3,770,739.

DESCRIPTION OF THE INVENTION This invention relates to new 1,2,4-oxadiazolyldiazines which may be illustrated by the following formula:

C 2 v N\ 11-0 c-R C 2 wherein R is selected from the group consisting ofpyridazinyl and pyrimidyl; Z is a trivalent radical selected from thegroup consisting of n l I ll N--O and O and the dotted line representsone double bond, the position of which is dependent upon the definitionof Z. When Z is I ll O-N suitable salts are the acetate, propionate,butyrate,

pamoate, mucate, citrate, malate, tosylate, phosphate, nitrate, sulfate,hydrobromide, hydroiodide, hydrochloride, etc.

The present compounds are somewhat soluble in hydrocarbon solvents. Thesalts of the compounds are slightly soluble in water.

The compounds of the present invention can be prepared by reaction ofcyclopropylcarboxylic acid anhydride and a diazinecarboxamidoxime atelevated temperature in the presence or absence of a solvent. Thecompounds are also prepared by the reaction of a diazinecarboxylic acidchloride or of an ester of a diazinecarboxylic acid withcyclopropylcarboxamidoxime in the presence of solvent at an elevatedtemperature.

These reactions are illustrated schematic-ally below:

CH HON l CH C H NC R 2 N I R o N RC wherein R is as defined above and Ris methyl or ethyl. Among the compounds considered to be within thescope of the present invention are:

3-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)pyridazine 3-( 3-cyclopropyI-l,2,4-oxadiazol-5-yl )pyridazine4-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)pyridazine4-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)pyridazine2-(5-cyclopropyl-I,2,4-oxadiazol-3-yl)pyrimidine2-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)pyrimidine 4-( 5-cyclopropyl-1,2,4-oxadiazol-3-yl )pyrimidine4-(3-cyclopropyl-l,2,4-oxadiazol-5-yl)pyrimidine5-(5-cyclopropyl-l,2,4-oxadiazol-3-yl)pyrimidine5-(3-cyclopropyl-I,2,4-oxadiazol-5-yl)pyrimidine The compounds of thisinvention show central nervous system depressant activity by theirability to protect warm-blooded animals, e.g., mice, from convulsionsand lethality resulting from the administration of strychnine sulfate[H. M. Hanson and Cv A. Stone, Animal and Clinical PharmacologicalTechniques in Drug Evaluation, Vol. I, J. H, Nodine and P. E. Siegler,Eds. Yearbook Medical Publishers, Inc, Chicago, III., 1964, p. 317].Graded dose levels of the compounds are administered intraperitoneallyin a 2% aqueous starch medium to groups of 10 mice at each dose.Strychnine sulfate, dissolved in aqueous saline is administeredsubcutaneously 30 minutes after drug treatment at a dose estimated tocause death in of the mice; namely, 1.25 mg. per kilogram of bodyweight. The medium effective dose is calculated by the method of J. T.Litchfield and F. Wilcoxon [,I. Pharmacol. Exp. Then, 96, 99 (1949)].These data on representative compounds of this invention are summarizedin Table I. It has been reported [M. I. Gluckman, Pharmacology ofoxazepam (Serax) an antianxiety agent, Curr. Therap. Res., 1,721 (1965)]that there is a high degree of correlation between anticonvulsant ef- Ifects in mice and antianxiety effects in higher warmblooded animals.

TABLE I-Continued Protection Against Death (aused liy Slryclininc Thepresent compounds may be dispensed in the form of capsules, tablets,pills, powders, dispersible granules and cachets. One or more of thefollowing may act' as solid pharmaceutical carrier flavoring agents,binders, tablet disintegrating agents, encapsulating material and thelike. Other solid carriers can be, for example, magnesium carbonate orstearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin,tragacanth, methyl cellulose, sodium carboxymethyl cellulose, etc.Preferably, the active component may represent a major portion of thedosage unit. The present compounds may be used in dosages which rangefrom about 0.1 to 100 mg./kg./per day in warm-blooded animals. Thewarm-blooded animals may include mice, rats, guinea pigs, dogs, rabbits,sheep, etc. A dosage unit may range from to 150 mg. given one or moretimes per day. It is usually preferable to give more than one dosageunit per day at predetermined intervals.

DETAILED DESCRIPTION The examples which follow describe the preparationof representative novel compounds of the present invention.

EXAMPLE 1 Preparation of 2-( S-cyclopropyl-l ,2,4-oxadiazol-3-yl)pyrazine A mixture of 6.9 g. of pyrazinecarboxamidoxime and 7.7 g. ofcyclopropanecarboxylic acid anhydride in 100 ml. of xylene is heatedunder reflux for 3 hours. The xylene is evaporated under reducedpressure and the residue is suspended in aqueous sodium carbonate. Themixture is filtered to collect tan crystals which are recrystallizedfrom isopropyl alcohol to give strawcolored crystals, melting point9598C. The compound forms a slightly water soluble hydrochloride salt.

EXAMPLE 2 Preparation of 2-( S-methyl-l ,2,4-o-xadiazol-3-yl )pyrazine Astirred mixture of 2.8 g. of pyrazinecarboxamidoxime and 2.0 g. ofacetic anhydride in 50 ml. of xylene is heated under reflux for 3 hours.The xylene isevaporated under reduced pressure and the residue isrecrystallized twice from isopropyl alcohol to give white crystals,melting point 100l04C.

EXAMPLE 3 Preparation of 2-(5-ethyl-1,2,4-oxadiazol-3-yl)pyrazine Astirred mixture of 2.8 g. of pyrazinecarboxamidoxime and 2.6 g. ofpropionic anhydride in 50 ml. of xylene is heated under reflux for 3hours and concentrated to a viscous liquid. The liquid is suspended inaqueous sodium carbonate and the mixture is extracted with chloroform.The chloroform solution is dried over anhydrous mangesium sulfate andconcentrated to a solid. Recrystallization from hexane gives whitecrystals, melting point 525 7C.

EXAMPLE 4 Preparation of 4-( 5-Cyclopropyl-1,2,4-oxadiazol-3-yl)pyridazine A mixture of 2.8 g. of4-p'yridazinecarboxamidoxime and 3.1 g. of cyclopropanecarboxylic acidanhydride in 50 ml. of xylene is heated under reflux for 3 hours. Themixture is filtered and the collected solid is suspended in aqueoussodium carbonate. The mixture is filtered and the collected solidpartially dissolved in hot ethanol and filtered. The filtrate isconcentrated to tan crystals which are recrystallized from ethanol togive creamcolored crystals, melting point 1 l5-l 17C. The compound formsa slightly water soluble sulfate salt, when treated with sulfuric acid.

EXAMPLE 5 Preparation of 4-(5-ethyl-1,2,4-oxadiazol-3-yl)pyridazine Amixture of 0.92 g. of 4- pyridazinecarboxamidoxime, 1.05 g., ofpropionic anhydride and 20 ml. of xylene is heated under reflux for 2hours. The mixture is washed with 1 N sodium hydroxide, the xylenesolution dried over mangesium sulfate and concentrated to give a tansolid. This solid is recrystallized from cyclohexane to give colorlessneedles, melting point 7374C.

EXAMPLE 6 Preparation of 4-(5-c'yclopropyl-l,2,4-oxadiazol-3-yl)pyrimidine A mixture of 1.4 g. of4-pyrimidinecarboxamidoxime and 1.5 g. of cyclopropanecarboxylic acidanhydride in 20 ml. of xylene is heated under reflux for 3 hours. The

mixture is concentrated to give a viscous, orange liquid which issuspended in aqueous sodium carbonate and then filtered to collect anorange solid. This solid is recrystallized from cyclohexane to give paleyellow crystals, melting point 8994C. The compound forms a sparinglywater soluble citrate salt.

EXAMPLE 7 Preparation of 2-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)pyrazineTo a mixture of 28.7 g. of pyrazinoyl chloride in ml. of xylene is addedslowly a solution of 20 g. of cyclopropanecarboxamidoxime in 100 ml. ofxylene. This mixture is heated under reflux for 3 hours, concentratedunder reduced pressure and the residue mixed with aqueous sodiumhydroxide. The mixture is filtered and the filtrate is extracted withchloroform. The chloroform solution is dried over magnesium sulfate andconcentrated under reduced pressure to give crude crystals, which arerecrystallized from cyclohexane to give light yellow crystals, meltingpoint 6164C.

EXAMPLE 8 Preparation of 2-( 3-Cyclopr0pyl-l,2,4-oxadiaz0l-5-yl)pyrazine To a mixture of 2.8 g. ofcyclopropanecarboxamidoxime hydrochloride and 2.8 g. of methylpyrazinoate in 50 ml. of toluene is added 2.2 g. of sodium methoxide.The mixture is heated under reflux for 30 minutes and then poured into100 ml. of water. The toluene phase is separated and the aqueous phaseis extracted with chloroform. The combined organic solutions are driedover magnesium sulfate and concentrated under reduced pressure to give asolid. This solid is recrystallized from cyclohexane to givecream-colored crystals, melting point 6668C. The compound forms aslightly water soluble phosphate salt, when treated with phsophoricacid.

We claim:

1. A cyclopropyl-l ,2,4-oxadiazolyldiazine of the formula:

wherein Z is a trivalent radical selected from the group consisting ofll l I ll NO and O-N;

1. A CYCLOPROPYL-1, 2, 4-OXADIAZOLYDIAZINE OF THE FORMULA:
 2. Thecyclopropyl-1,2,4-oxadiazolylpyrimidine according to claim 1:4-(5-cyclopropyl-1,2,4-oxadiazol-3-yl)pyrimidine.